AR035798A1 - INHIBITING COMPOUNDS OF ALDOSA REDUCTASA OF THE PIRIDAZIN-3-ONAS GROUP, PHARMACEUTICAL COMPOSITIONS AND METHODS OF TREATMENT OF ISCHEMIA AND DIABETIC DISEASES - Google Patents

INHIBITING COMPOUNDS OF ALDOSA REDUCTASA OF THE PIRIDAZIN-3-ONAS GROUP, PHARMACEUTICAL COMPOSITIONS AND METHODS OF TREATMENT OF ISCHEMIA AND DIABETIC DISEASES

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AR035798A1
AR035798A1 ARP020101134A ARP020101134A AR035798A1 AR 035798 A1 AR035798 A1 AR 035798A1 AR P020101134 A ARP020101134 A AR P020101134A AR P020101134 A ARP020101134 A AR P020101134A AR 035798 A1 AR035798 A1 AR 035798A1
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alkyl
optionally substituted
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alkoxy
hydroxy
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Pfizer Prod Inc
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    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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Abstract

Compuestos de piridazin-3-ona, a composiciones farmacéuticas que comprenden esos compuestos y a métodos de utilización de tales compuestos y composiciones para inhibir la aldosa reductasa, disminuir los niveles de sorbitol y, por tanto, hacer descender los niveles de fructosa, y/o tratar o prevenir complicaciones diabéticas tales como neuropatía diabética, retinopatía diabética, nefropatía diabética, cardiomiopatía diabética, microangiopatía diabética y macroangiopatía diabética, en los mamíferos. Se describen también métodos para proporcionar cardioprotección a sujetos no aquejados de diabetes. Se refiere también a composiciones farmacéuticas y a kits que comprenden una combinación de un inhibidor de la aldosa reductasa (ARI), y un inhibidor de la sorbitol deshidrogenasa, y a métodos de utilización de tales composiciones o kits para tratar o prevenir las complicaciones diabéticas anteriores en los mamíferos. Se refiere también a otras combinaciones con los ARIs de la presente, incluyendo combinaciones con agonistas de la adenosina, inhibidores de NHE-1, inhibidores de la glicógeno fosforilasa, inhibidores selectivos de la reabsorción de serotonina, agonistas del GABA, agentes antihipertensivos, inhibidores de la 3-hidroxi-3-metilglutaril coenzima A reductasa, e inhibidores de la fosfodiesterasa-5, y a agentes de disminución de la glucosa. Un compuesto de Fórmula (1), uno de sus profármacos o una sal farmacéuticamente aceptable de dicho compuesto o dicho profármaco, en la que: A es S, SO ó SO2; R1 y R2 son, cada uno independientemente, hidrógeno o metilo; R3 es Het1, -CHR4Het1 ó NR6R7; R4 es hidrógeno o alquilo C1-3; R6 es alquilo C1-6, arilo o Het2; R7 es Het3; Het1 es piridilo, pirimidilo, pirazinilo, piridazinilo, quinolilo, isoquinolilo, quinazolilo, quinoxalilo, ftalazinilo, cinolinilo, naftiridinilo, pteridinilo, pirazinopirazinilo, pirazinopiridazinilo, pirimidopiridazinilo, pirimidopirimidilo, piridopirimidilo, piridopirazinilo, piridopiridazinilo, pirrolilo, furanilo, tienilo, imidazolilo, oxazolilo, tiazolilo, pirazolilo, isoxazolilo, isotiazolilo, triazolilo, oxadiazolilo, tiadiazolilo, tetrazolilo, indolilo, benzofuranilo, benzotienilo, bencimidazolilo, benzoxazolilo, benzotiazolilo, indazolilo, bencisoxazolilo, bencisotiazolilo, pirrolopiridilo, furopiridilo, tienopiridilo, imidazolopiridilo, oxazolopiridilo, tiazolopiridilo, pirazolopiridilo, isoxazolopiridilo, isotiazolopiridilo, pirrolopirimidilo, furopirimidilo, tienopirimidilo, imidazolopirimidilo, oxazolopirimidilo, tiazolopirimidilo, pirazolopirimidilo, isoxazolopirimidilo, isotiazolopirimidilo, pirrolopirazinilo, furopirazinilo, tienopirazinilo, imidazolopirazinilo, oxazolopirazinilo, tiazolopirazinilo, pirazolopirazinilo, isoxazolopirazinilo, isotiazolopirazinilo, pirrolopiridazinilo, furopiridazinilo, tienopiridazinilo, imidazolopiridazinilo, oxazolopiridazinilo, tiazolopiridazinilo, pirazolopiridazinilo, isoxazolopiridazinilo o isotiazolopiridazinilo; Het1 está opcionalmente sustituido con hasta un total de cuatro sustituyentes seleccionados independientemente, cada uno de ellos, entre halo, formilo, alcoxi(C1-6)carbonilo, alquenil(C1-6)oxicarbonilo, alcoxi(C1-4)-alquilo (C1-4), C(OH)R12R13, alquil(C1-4)carbonilamido, cicloalquil(C3-7)carbonilamido, fenilcarbonilamido, bencilo, fenilo, naftilo, imidazolilo, piridilo, triazolilo, bencimidazolilo, oxazolilo, isoxazolilo, tiazolilo, oxadiazolilo, tiadiazolilo, tetrazolilo, tienilo, benzotiazolilo, pirrolilo, pirazolilo, quinolilo, isoquinolilo, benzoxazolilo, piridazinilo, piridiloxi, piridilsulfonilo, furanilo, fenoxi, tiofenoxi, alquil(C1-4)sulfenilo, alquil(C1-4)sulfonilo, cicloalquilo C3-7, alquilo C1-6 opcionalmente sustituido con hasta tres sustituyentes fluoro, o alcoxi C1-4 opcionalmente sustituido con hasta cinco sustituyentes fluoro; dichos bencilo, fenilo, naftilo, imidazolilo, piridilo, triazolilo, bencimidazolilo, oxazolilo, isoxazolilo, tiazolilo, oxadiazolilo, tiadiazolilo, tetrazolilo, tienilo, benzotiazolilo, pirrolilo, pirazolilo, quinolilo, isoquinolilo, benzoxazolilo, piridazinilo, piridiloxi, piridilsulfonilo, furanilo, fenoxi tiofenoxi, en la definición de sustituyentes para Het1 están opcionalmente sustituidos con hasta tres sustituyentes seleccionados independientemente entre hidroxi, halo, hidroxi-alquilo C1-4, alcoxi(C1-4)-alquilo(C1-4), alquil(C1-6)sulfenilo, alquil(C1-6)sulfinilo, alquil(C1-6)sulfonilo, alquilo C1-6 opcionalmente sustituido con hasta cinco sustituyentes fluoro y alcoxi C1-6 opcionalmente sustituido con hasta cinco sustituyentes fluoro; dichos imidazolilo, oxazolilo, isoxazolilo, tiazolilo y pirazolilo en la definición de sustituyentes para Het1 están opcionalmente sustituidos con hasta dos sustituyentes seleccionados independientemente entre hidroxi, halo, alquilo C1-4, hidroxi-alquilo C1-4, alcoxi(C1-4)-alquilo(C1-4), alquil(C1-4)-fenilo opcionalmente sustituido en la parte de fenilo con un Cl, Br, OMe, Me ó SO2-fenilo en el que dicho SO2-fenilo está opcionalmente sustituido en la parte de fenilo con un Cl, Br, OMe, Me, alquilo C1-4 opcionalmente sustituido con hasta cinco sustituyentes fluoro, o alcoxi C1-4 opcionalmente sustituido con hasta tres sustituyentes fluoro; R12 y R13 son, cada uno independientemente, hidrógeno o alquilo C1-4; Het2 y Het3 son, cada uno independientemente, imidazolilo, piridilo, triazolilo, bencimidazolilo, oxazolilo, isoxazolilo, tiazolilo, oxadiazolilo, tiadiazolilo, tetrazolilo, tienilo, benzotiazolilo, pirrolilo, pirazolilo, quinolilo, isoquinolilo, benzoxazolilo, piridazinilo, piridiloxi, piridilsulfonilo, furanilo, fenoxi y tiofenoxi; Het2 y Het3 están, cada uno independientemente, opcionalmente sustituido con hasta un total de cuatro sustituyentes seleccionados independientemente cada uno de ellos entre halo, formilo, alcoxi(C1-4)carbonilo, alquilenil(C1-6)oxi-carbonilo, alcoxi(C1-4)-alquilo(C1-4), C(OH)R18R19, alquil(C1-4)carbonilamido, cicloalquil(C3-7)carbonilamido, fenilcarbonilamido, fenilo, naftilo, imidazolilo, piridilo, triazolilo, bencimidazolilo, oxazolilo, isoxazolilo, tiazolilo, oxadiazolilo, tiadiazolilo, tetrazolilo, tienilo, benzotiazolilo, pirrolilo, pirazolilo, quinolilo, isoquinolilo, benzoxazolilo, piridazinilo, piridiloxi, piridilsulfonilo, furanilo, fenoxi, tiofenoxi, alquil(C1-4)sulfenilo, alquil(C1-4)sulfonilo, cicloalquilo C3-7, alquilo C1-4 opcionalmente sustituido con hasta tres sustituyentes fluoro o alcoxi C1-4 opcionalmente sustituido con hasta cinco sustituyentes fluoro; dichos fenilo, naftilo, imidazolilo, piridilo, triazolilo, bencimidazolilo, oxazolilo, isoxazolilo, tiazolilo, oxadiazolilo, tiadiazolilo, tetrazolilo, tienilo, benzotiazolilo, pirrolilo, pirazolilo, quinolilo, isoquinolilo, benzoxazolilo, piridazinilo, piridiloxi, piridilsulfonilo, furanilo, fenoxi, tiofenoxi, en la definición de sustituyentes para Het2 y Het3 están opcionalmente sustituidos con hasta tres sustituyentes seleccionados independientemente entre hidroxi, halo, hidroxi-alquilo C1-4, alcoxi(C1-4)-alquilo(C1-4), alquilo C1-4 opcionalmente sustituido con hasta cinco sustituyentes fluoro y alcoxi C1-4 opcionalmente sustituido con hasta cinco sustituyentes fluoro; dichos imidazolilo, oxazolilo, isoxazolilo, tiazolilo y pirazolilo en la definición de sustituyentes para Het2 y Het3 están opcionalmente sustituidos con hasta dos sustituyentes seleccionados independientemente entre hidroxi, halo, hidroxi-alquilo C1-4, alcoxi(C1-4)-alquilo(C1-4), alquilo C1-4 opcionalmente sustituido con hasta cinco sustituyentes fluoro y alcoxi C1-4 opcionalmente sustituido con hasta tres sustituyentes fluoro; y R18 y R19 son, cada uno independientemente, hidrógeno o alquilo C1-4; con tal que cuando R3 es NR6R7, entonces A es SO2.Pyridazin-3-one compounds, pharmaceutical compositions comprising those compounds and methods of using such compounds and compositions to inhibit aldose reductase, decrease sorbitol levels and, therefore, lower fructose levels, and / or treat or prevent diabetic complications such as diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic cardiomyopathy, diabetic microangiopathy and diabetic macroangiopathy, in mammals. Methods for providing cardioprotection to subjects not suffering from diabetes are also described. It also refers to pharmaceutical compositions and kits comprising a combination of an aldose reductase inhibitor (ARI), and a sorbitol dehydrogenase inhibitor, and methods of using such compositions or kits to treat or prevent previous diabetic complications in the mammals It also refers to other combinations with the ARIs of the present, including combinations with adenosine agonists, NHE-1 inhibitors, glycogen phosphorylase inhibitors, selective serotonin reabsorption inhibitors, GABA agonists, antihypertensive agents, inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, and phosphodiesterase-5 inhibitors, and glucose lowering agents. A compound of Formula (1), one of its prodrugs or a pharmaceutically acceptable salt of said compound or said prodrug, wherein: A is S, SO or SO2; R1 and R2 are each independently hydrogen or methyl; R3 is Het1, -CHR4Het1 or NR6R7; R4 is hydrogen or C1-3 alkyl; R6 is C1-6 alkyl, aryl or Het2; R7 is Het3; Het1 is pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, quinazolyl, quinoxalyl, phthalazinyl, cinnolinyl, naphthyridinyl, pteridinyl, pyrazinopyrazinyl, pyrazinopyridazinyl, pyrimidopyridazinyl, pyrimidopyrimidyl, pyridopyrimidyl, pyridopyrazinyl, pyridopyridazinyl, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, pyrrolopyridyl, furopyridyl, thienopyridyl, imidazolopiridilo, oxazolopyridyl, thiazolopyridyl, pyrazolopyridyl, isoxazolopiridilo, isothiazolopyridyl, pyrrolopyrimidyl, furopyrimidyl, thienopyrimidyl, imidazolopyrimidyl, oxazolopyrimidyl, thiazolopyrimidyl, pyrazolopyrimidyl, isoxazolopyrimidyl, isothiazolopyrimidyl, pyrrolopyrazinyl, thiopyrnozinyl, furopyrazine opirazinyl, thiazolopirazinyl, pyrazolopyrazinyl, isoxazolopyrazinyl, isothiazolopyrazinyl, pyrrolopyridazinyl, furopyridazinyl, thienopyrididazinyl, imidazolopyridazinyl, oxazolopyridazinyl, thiazolopyridazinyl, isoylopyridazinyl; Het1 is optionally substituted with up to a total of four independently selected substituents, each of them, from halo, formyl, (C1-6) alkoxycarbonyl, (C1-6) alkenyl oxycarbonyl, (C1-4) alkoxy (C1 -4), C (OH) R12R13, (C1-4) alkylcarbonylamide, cycloalkyl (C3-7) carbonylamide, phenylcarbonylamide, benzyl, phenyl, naphthyl, imidazolyl, pyridyl, triazolyl, benzimidazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl thiadiazolyl, tetrazolyl, thienyl, benzothiazolyl, pyrrolyl, pyrazolyl, quinolyl, isoquinolyl, benzoxazolyl, pyridazinyl, pyridyloxy, pyridylsulfonyl, furanyl, phenoxy, thiophenoxy, alkyl (C1-4) sulfenyl, alkyl (C1-4) sulfonyl, cycloalkyl-7 , C1-6 alkyl optionally substituted with up to three fluoro substituents, or C1-4 alkoxy optionally substituted with up to five fluoro substituents; said benzyl, phenyl, naphthyl, imidazolyl, pyridyl, triazolyl, benzimidazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, thienyl, benzothiazolyl, pyrrolyl, pyrazolyl, quinolyl, isoquinolyl, benzoxazolyl, pyridazinyl, pyridyloxy, pyridylsulfonyl, furanyl, phenoxy thiophenoxy, in the definition of substituents for Het1 are optionally substituted with up to three substituents independently selected from hydroxy, halo, hydroxy-C1-4 alkyl, (C1-4) alkoxy (C1-4) alkyl, (C1-6) alkyl sulfenyl, (C1-6) alkyl sulfinyl, (C1-6) alkyl sulfonyl, C1-6 alkyl optionally substituted with up to five fluoro substituents and C1-6 alkoxy optionally substituted with up to five fluoro substituents; said imidazolyl, oxazolyl, isoxazolyl, thiazolyl and pyrazolyl in the definition of substituents for Het1 are optionally substituted with up to two substituents independently selected from hydroxy, halo, C1-4 alkyl, hydroxy-C1-4 alkyl, (C1-4) alkoxy - (C1-4) alkyl, (C1-4) alkyl -phenyl optionally substituted in the phenyl part with a Cl, Br, OMe, Me or SO2-phenyl in which said SO2-phenyl is optionally substituted in the phenyl part with a Cl, Br, OMe, Me, C1-4 alkyl optionally substituted with up to five fluoro substituents, or C1-4 alkoxy optionally substituted with up to three fluoro substituents; R12 and R13 are each independently hydrogen or C1-4 alkyl; Het2 and Het3 are, each independently, imidazolyl, pyridyl, triazolyl, benzimidazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, thienyl, benzothiazolyl, pyrrolyl, pyrazolyl, quinolyl, isoquinolyl, pyridaxylidenyl, pyridaxyl, pyridaxyl, pyridyloxy; , phenoxy and thiophenoxy; Het2 and Het3 are, each independently, optionally substituted with up to a total of four substituents each independently selected from halo, formyl, (C1-4) alkoxycarbonyl, (C1-6) alkylenyl oxycarbonyl, C1 (alkoxy) -4) - (C1-4) alkyl, C (OH) R18R19, (C1-4) alkylcarbonylamide, cycloalkyl (C3-7) carbonylamido, phenylcarbonylamide, phenyl, naphthyl, imidazolyl, pyridyl, triazolyl, benzimidazolyl, oxazolyl, isoxazolyl , thiazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, thienyl, benzothiazolyl, pyrrolyl, pyrazolyl, quinolyl, isoquinolyl, benzoxazolyl, pyridazinyl, pyridyloxy, pyridylsulfonyl, furanyl, phenoxy, thiophenoxy, C1-4 (C1-4) sulfenyl, sulfenyl, sulfonyl, C1-4 alkyl , C3-7 cycloalkyl, C1-4 alkyl optionally substituted with up to three fluoro substituents or C1-4 alkoxy optionally substituted with up to five fluoro substituents; said phenyl, naphthyl, imidazolyl, pyridyl, triazolyl, benzimidazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, thienyl, benzothiazolyl, pyrrolyl, pyrazolyl, quinolyl, isoquinolyl, benzoxazolyl, pyriloxyloxyphenoxy, pyriloxyloxyphenoxy, pyriloxyloxyphenoxy, pyriloxyloxyphenoxy, pyriloxyloxyphenoxy, pyriloxyloxyphenoxy, pyriloxyloxyphenoxy, pyryloxyloxyloxyphenyloxyloxyphenyloxyloxyphenyloxyloxyphenyloxyloxyphenyloxyloxyphenyloxyloxyphenyloxyloxyphenyloxy group , in the definition of substituents for Het2 and Het3 are optionally substituted with up to three substituents independently selected from hydroxy, halo, hydroxy-C1-4 alkyl, (C1-4) alkoxy-(C1-4) alkyl, optionally C1-4 alkyl substituted with up to five fluoro substituents and C1-4 alkoxy optionally substituted with up to five fluoro substituents; said imidazolyl, oxazolyl, isoxazolyl, thiazolyl and pyrazolyl in the definition of substituents for Het2 and Het3 are optionally substituted with up to two substituents independently selected from hydroxy, halo, hydroxy-C1-4alkyl, (C1-4) alkoxy (C1 -4), C1-4 alkyl optionally substituted with up to five fluoro substituents and C1-4 alkoxy optionally substituted with up to three fluoro substituents; and R18 and R19 are each independently hydrogen or C1-4 alkyl; provided that when R3 is NR6R7, then A is SO2.

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